1. Field of the Invention
The present invention relates to stable compositions of hydrolytically unstable pharmaceutical compounds. In particular, this invention relates to stable compositions containing positively charged, hydrolytically unstable drug compounds and sulfated polyvinyl alcohol polymers.
2. Description of Related Art
Epinephrine is an ophthalmic drug which has been Used for many years in the treatment of glaucoma. When topically administered to the eye, epinephrine can cause irritation, tearing, conjunctival hyperemia, and other side effects. The dipivalyl ester of epinephrine has been developed as a prodrug in an attempt to eliminate epinephrine's undesirable side effects. This epinephrine prodrug is known as dipivefrine hydrochloride or dipivalyl epinephrine ("DPE").
One of the problems associated with DPE in solution, however, is its instability due to ester hydrolysis and/or oxidation, causing a relatively short shelf-life.
One known method of improving the stability and/or comfort of certain pharmaceutical drug compounds is complexing the drug compound with certain ion-exchange resins. Such a method is disclosed in, for example, U.S. Pat. Nos. 4,911,920 and 5,093,126, where sustained release ophthalmic formulations of topical anti-glaucoma drugs include a water insoluble ion-exchange resin such as a sodium poly(styrenedivinyl benzene) sulfonate, to provide an additional means of sustained release and to improve comfort.
Ophthalmic solutions containing polystyrene sulfonate compounds are disclosed in U.S. Pat. No. 3,987,163. The reference solutions can be used to treat "dry eye" or as a carrier for ophthalmic medicaments. When used as a carrier, the reference solutions provide prolonged duration of medicament activity.
European Patent Application Publication No. 0 392 487 discloses a stabilized pharmaceutical composition containing an anthracycline antibiotic having an amino sugar residue and a certain kind of water-soluble polyanion capable of at least 40% interacting with the antibiotic. The water-soluble polyanions are natural and synthetic polymers having negatively charged acidic residues, such as sulfuric or sulfonic acid residues, and have a molecular weight of 500 to 2,000,000. Listed examples of natural polyanions include polysaccharides preferably having 1.5 to 3 sulfuric acid residues per repeating unit sugar. Dextransulfate is listed as one example of a natural macromolecular polyanion. The synthetic polymers include, among others, polystyrene and polyvinyl alcohol each preferably having 0.2 to 1.0 sulfuric acid residue per monomer unit. The reference anthracycline antibiotic composition possess improved stability in the neutral pH region.